When should you test your patients for breast cancer genes?
By Margie Patlak
Since the mid-1990s, when testing for breast cancer (BRCA) genes 1 and 2 first became available, doctors have faced a growing quandary: Should they conduct a test that many women want but that helps only a select few?
Despite popular misconceptions, BRCA tests can't accurately predict whether a woman will get breast cancer. In stark contrast to most clinical tests available, these tests have so many limitations, uncertainties and caveats that they are only truly useful for a select group of women.
Because of this confusion, experts say, it's critical that physicians understand genetic testing. They say that doctors—particularly internists—need to help guide patients' decisions about whether to undergo testing, and they need to appropriately refer patients to specialists. As a result, physicians need to know what BRCA tests can—and cannot—reveal about a woman's risk of getting breast and ovarian cancer.
While diagnostic tests usually give yes-no answers, many genetic tests can only spit out probabilities for specific populations. "If you don't understand the limitations of the tests, you can't extract the clinical benefits from them," explained geneticist Matthew R. Taylor, MD, director of the adult genetics section of the University of Colorado Health Sciences Center.
In addition, because the tests are so new, no definitive clinical studies have assessed the best interventions for women who do test positive for the breast cancer genes. This means doctors must rely on expert opinion to determine how to best treat these women, but these opinions continually shift as more information surfaces.
Typically, however, that message falls on deaf ears. "Women take these tests as gospel," said Paul Wolpe, PhD, a bioethicist at the University of Pennsylvania in Philadelphia. "They are walking into their doctor's offices and demanding the tests, and it's very difficult for doctors to say 'no' to that."
What BRCA genes mean
A common misperception about BRCA mutations is that they cause breast or ovarian cancer. The reality, however, is that these mutations don't actually trigger cancers, but merely set the stage.
Researchers think that the BRCA 1 and 2 genes normally help cells repair damaged DNA. When the BRCA 1 or 2 genes significantly mutate, however, these genetic repairs are never made. As a result, damaged cells may develop into cancers.
When talking to patients, it's critical to emphasize that in most people, BRCA mutations are rare. Only 5% to 10% of breast cancers and less than 5% of ovarian cancers, for example, can be attributed to mutated BRCA 1 or 2 genes.
For families plagued by an inherited susceptibility to breast or ovarian cancer, however, mutated BRCA genes are the root cause of most cancers. Ashkenazi Jewish women—those with eastern European ancestry—appear to be more likely to harbor 1 and 2 gene mutations, which occur in 2% of these women.
BRCA genes are dominant and passed on from both the mother and father. A child of a parent with the mutated gene has a 50% chance of inheriting it. (Men with mutated BRCA genes also have a more heightened risk for breast cancer than men who lack the mutations, but their chances of developing the cancer are still slim. Men with these abnormal genes, however, may be more susceptible to prostate or colon cancer.)
When BRCA testing first entered the market about five years ago, it was widely reported that a positive result meant an 85% risk of women developing breast cancer by age 70 or a 44% risk of developing ovarian cancer by the same age. That risk, however, was inflated because it was based on studies of Utah families exceptionally inundated with breast and ovarian cancer.
Today, researchers say that the percentage of women carrying BRCA mutations who will eventually develop breast or ovarian cancer varies widely. In part, it depends on specific genetic mutations, other inherited genes, and other factors such as environmental causes. The lifetime risks for women with BRCA 1 and 2 mutations fall within a wider range of 36% to 85% for breast cancer and 16% to 60% for ovarian cancer.
Complicating matters is the fact that most women who test positive for a BRCA mutation will not know where within this wide range their particular risk for breast cancer lies. But as medical oncologist Mary B. Daly, FACP, of Philadelphia's Fox Chase Cancer Center pointed out, "Even if a patient is at the low end of the scale, she has three times the risk of developing breast cancer as the average woman, and that's something you don't want to ignore."
You should suspect BRCA mutations—and consider testing—if patients have one of the following red flags in their personal or family medical histories: breast or ovarian cancer before age 50, bilateral breast cancer, several generations of close relatives with breast or ovarian cancer, or a relative who has had both breast and ovarian cancer. Extensive histories are often needed to detect the inherited breast-ovarian cancer syndrome.
If you're taking a family history to determine whether a patient is prone to BRCA mutations, however, plan to do some digging. "If the doctor only asks a patient what her mother or father died of," explained Dr. Taylor, "the physician may miss the fact that the patient's father had three sisters who died at a young age from breast cancer."
BRCA testing is not usually recommended unless a patient has at least a 10% chance of having a BRCA mutation. You can calculate risk by performing a pedigree analysis using specialized computer software that is readily available to physicians. (For more on testing resources, see "Genetic testing Web resources," at www.acponline.org/journals/news/dec01/cancer.htm#resources.)
Unless you have a strong interest in this area, however, experts say you should probably refer patients you suspect of having BRCA mutations to genetic counselors, geneticists or oncologists who specialize in such analyses before testing is performed.
Many of the shortcomings of BRCA tests come to light only after the results come in. The fact that negative results are not always true negatives is particularly frustrating.
For example, if tests show your patient doesn't have the same BRCA mutation as a relative with ovarian or breast cancer who tested for BRCA mutations, it is likely that she truly will escape the heightened cancer risk legacy of her relatives. But in high-risk families, it's often not possible to have a family member with breast or ovarian cancer tested for a BRCA mutation because the relative isn't living or simply refuses to be tested. If your patient tests negative but you have no test results from family members, she could still have the mutation that heightens breast and ovarian cancer susceptibility in her family. That is because BRCA tests cannot detect all genetic mutations. If her family's particular mutation falls outside the range of mutations currently detectable, she will test negative yet still have heightened breast and ovarian cancer risk. Indeed, BRCA testing is blind to about one-third of all mutations.
In addition, more than one in 10 BRCA tests yields inconclusive results because researchers simply don't know whether the BRCA mutation they detect is clinically significant. (Not all BRCA mutations will increase a person's risk of breast or ovarian cancer.)
BRCA tests also can't predict a woman's risk of developing a breast or ovarian cancer due to a reason other than BRCA mutations. That's particularly problematic because most breast and ovarian cancers are caused by something other than a BRCA mutation. Even if a women tests negative for BRCA mutations, she still has an 11% to 12% risk of developing breast cancer or a 1% to 2% risk of developing ovarian cancer in her lifetime.
If your patient tests positive for BRCA mutations, the implications can be equally uncertain. Women who test positive have a few basic options.
- Screening. While the most obvious course of action would seem to be heightened screening for cancers, the data do not conclusively show that it will help.
The Cancer Genetics Studies Consortium (CGSC) of the National Human Genome Research Institute recommends that women who test positive for BRCA mutations practice monthly breast self-exams beginning at ages 18 to 21. The consortium also recommends semiannual or annual clinical breast exams and annual mammography starting between ages 25 and 35.
Whether any of these screening measures will make a significant dent in women's mortality, however, is unknown. No study has ever found breast self-exams to be effective. Clinical breast exams are only likely to detect a small percentage of cancers at an early stage, and mammography is notoriously insensitive in the dense breast tissue typically found in young women.
Some even speculate that certain forms of screening may be particularly risky for BRCA-positive women, fearing that mammography radiation exposure might actually boost BRCA-positive women's risk of breast cancer. (Researchers hypothesize that gene mutations might hamper the repair of cell damage from X-rays.)
But Fox Chase's Dr. Daly, who is a CGSC member, pointed out that no studies have proven mammograms cause radiation damage. She also noted that one study found that BRCA-positive women who received radiation therapy for breast cancer did not have increased risk of recurrence or radiation toxicity.
The consortium also recommends BRCA-positive women undergo annual or semi-annual pelvic exams beginning at age 25 to 35. These exams should include transvaginal ultrasound examination with color Doppler, and blood tests for a tumor antigen known as CA-125. The problem is that these tests often cannot detect ovarian cancer at an early enough stage to save women's lives.
- Drug therapy. Researchers are testing tamoxifen to reduce breast cancer in BRCA-positive women. Researchers hypothesize that because most BRCA 1-related breast cancers are not estrogen receptor positive, tamoxifen may not be effective for women with mutations in this gene. A recent study found this to be true. However, this research, which appeared in the Nov. 14 Journal of the American Medical Association, found that tamoxifen significantly reduced the incidence of tumors in women with BRCA 2 mutations.
- Surgery. Even dramatic surgical measures cannot guarantee that BRCA-positive women will avoid breast or ovarian cancer because of residual tissue left behind. Ovarian ablations reduce ovarian cancer risk by about 95% and can also cut in half the risk of breast cancer. Bilateral mastectomies reduce breast cancer risk by about 90%. (Although BRCA-positive women rarely opt for bilateral mastectomies, said Dr. Daly, many women are receptive to ovarian ablation if they are finished bearing children.)
The consortium recommends that women with BRCA mutations be offered these surgical options, but it notes that patients themselves should decide whether to pursue surgery.
Pros and cons of testing
Despite the lack of long-term data and follow-up options, experts note that BRCA testing can serve some useful purposes. When women come from high-risk families in which a family member with breast or ovarian cancer has been shown to have a clinically relevant BRCA mutation, Dr. Taylor from the University of Colorado said, they can benefit from BRCA testing.
For some, a negative result will ease their fear of being at risk of having the mutation. For those who test positive for the mutation, "You can tell them to start doing early breast and ovarian cancer screening," he said.
Dr. Wolpe pointed out that a true negative BRCA test result for a woman from a high-risk family can be extremely beneficial if the woman was considering having a prophylactic mastectomy or oophorectomy before testing. "It would be a good reason for her to reconsider surgery," he said.
Despite these benefits, some experts worry that women who test negative for BRCA mutations will erroneously assume their lifetime breast cancer risk is so low that they don't have to bother getting regular mammograms. Dr. Wolpe also said he worries about how women will interpret the wide range of risk probabilities if they test positive.
"People tend not to know what to do with probabilities and ranges of risk," he explained. "If everyone actually understood the odds, no one would ever buy a state lottery ticket, yet millions do."
Dr. Wolpe conducted a study of women who were offered BRCA testing and found that many of them—and their doctors—decided whether or not to test for the wrong reasons. Some women opted not to be tested, for example, because they already had breast cancer and assumed they couldn't get it again. Other women were tested who didn't have a family or personal history indicative of BRCA mutations. If these women tested positive, they were erroneously given the same chances of developing breast or ovarian cancer as someone in an extremely high-risk group.
"I'm not suggesting that we should never recommend that women take these tests," Dr. Wolpe said. "But I think they are being taken much too cavalierly, and their results are being used to make bad medical management decisions much too often."
Experts interviewed for this story all emphasized that one way to avoid that problem is to ensure that every woman considering BRCA testing gets extensive genetic counseling before and, if she then opts to be tested, after she receives testing. Most university hospitals offer such genetic counseling; so do some geneticists and oncologists.
But genetic counseling doesn't get general internists off the hook completely. "Many internists aren't sufficiently familiar with genetics to properly address the complexities of genetic testing, and they are going to have to get up to speed," noted Dr. Taylor. BRCA 1 and BRCA 2, after all, are just two of several hundred genetic tests currently available, and more are added each day.
"We have to challenge ourselves to use these tests positively," Dr. Daly explained. "We'll make mistakes in the beginning, but that's how you learn."
"The long-term data you like to see for medical tests or procedures usually takes 20 or 30 years to accrue," Dr. Taylor explained, "but this testing is being done in real time. That's why it's very much a brave new world, and we have to figure things out as we go along. Nobody ever said that the genetics knowledge coming out now is going to make things simpler anytime soon."
Margie Patlak is a freelance science writer in Elkins Park, Pa.
The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of the ACP-ASIM.
Over five years ago, testing for mutations in the breast cancer susceptibility genes BRCA 1 and 2 became available outside of the research setting. Because BRCA testing can indicate that certain women are highly susceptible to developing breast cancer in their lifetimes, many feared that health insurers could alter their coverage based on BRCA test results, possibly limiting or denying coverage for those who test positive.
Because of these and other concerns, Congress passed the Health Insurance Portability and Accountability Act of 1996 (HIPPA). This bill makes it illegal for health plans-the source of coverage for most Americans-to consider genetic information a pre-existing condition or use it to deny or limit coverage. Nearly four-fifths of all states have passed similar anti-genetic discrimination laws as an extra safeguard.
"Insurance companies are actually taking a very proactive stance on this," said Mary Daly, MD, a medical oncologist at Fox Chase Cancer Center in Philadelphia. "They claim they will support women getting tested so they can do all the preventive care that might prevent cancer." So far, there have been no documented cases of health insurers using BRCA test results to deny or limit coverage.
Most major health insurers will pay for BRCA testing, which can cost more than $2,000, if a woman has 10% or greater chance of harboring BRCA 1 or 2 mutations, which increase cancer risk. Insurers typically calculate these odds using a pedigree analysis and software to examine a woman's risk factors and prior BRCA test results. If women test positive, most health insurers will also pay for the heightened breast and ovarian cancer surveillance recommended by experts, Dr. Daly said.
Dr. Daly has also found insurers receptive to covering the costs associated with prophylactic oophorectomies and mastectomies. Her only complaint? Insurers often pay little to nothing for the genetic counseling that should be done before and after BRCA testing. Experts say that such genetic counseling is crucial for BRCA tests to be used properly.
- The AMA offers genetics education resources, genetics policy, applied genetics, and links to relevant medical specialty society genetics sites on the genetics and molecular medicine part of its Web site.
- GeneTests-GeneClinics offers an online directory of laboratories that perform disease-specific clinical and research testing of inherited disorders. The site also contains a directory of genetic clinics and information about issues encountered in genetic testing and genetic counseling.
- The Johns Hopkins University Bloomberg School of Public Health offers BRCAPRO software, which assesses BRCA testing options for women at high risk of hereditary breast and ovarian cancer. The software is particularly useful for calculating a woman's likelihood of inheriting BRCA 1 or 2 mutations.
- The National Cancer Institute has a directory of specially trained genetic counselors, nurses or other health care professionals.
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